Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs) and for thyroid-stimulating hormone (TSH-R) as model 7TMRs to study their structure and function. During this year, we have studied several new aspects of the structure and function of these receptors. 1) We identified a cohort of amino acid residues within the human TSH-R that when mutated change the signaling properties of TSH-R and showed that these are in a domain within the transmembrane helical bundle that surround the putative binding pocket that we identified previously for small molecule ligands. This finding is likely generally applicable to all GPCRs. 2) In a follow-up study, we showed that amino acid residues within the transmembrane helical bundle of TSH-R inhibited activation of the receptor. Based on our research into TSH-R, we were invited to contribute a review article on small molecule ligands of GPCRs. 3) It was recently reported that three GPCRs signal persistently when exposed to their cognate ligands and it was suggested that persistent signaling was dependent on receptor internalization. Because of the important implications of the conclusion that persistent GPCR signaling was dependent upon internalization, we studied this phenomenon. We showed that persistent cAMP signaling by TSH-R was not dependent on internalization.